CN113230459A - Injectable myocardial repair hydrogel and preparation method thereof - Google Patents
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Abstract
The invention relates to the technical field of bionic materials, in particular to injectable myocardial repair hydrogel and a preparation method thereof. The injectable myocardial repair hydrogel comprises the following components in parts by weight: 30-60 parts of allyl gelatin, 20-50 parts of oxidized dextran and 3-15 parts of oxidized graphene. The injectable myocardium repairing hydrogel has the conductive characteristic similar to that of myocardial cells, is favorable for the transmission of electric signals between cells, has flexibility more conforming to the natural myocardium, and is favorable for the proliferation of the myocardial cells.
Description
Technical Field
The invention relates to the technical field of bionic materials, in particular to injectable myocardial repair hydrogel and a preparation method thereof.
Background
The native myocardium is an electrically active tissue in which purkinje fibers with electrical conduction function are distributed. Electrical signals from the sinoatrial node, when they pass through the myocardium, induce cardiomyocyte synchronous contraction through "excitatory-contractile" coupling. Meanwhile, the myocardial tissue has excellent mechanical strength and can support continuous contraction and relaxation during the heart beating. Therefore, the scaffold material for the construction of the engineered myocardial tissue should have both excellent electrical conductivity and elastic modulus.
The biological scaffold plays a critical role in tissue engineering reconstruction, can be used as a drug carrier, creates a bionic biological microenvironment for cells, is beneficial to the transmission of nutrient substances and the transportation of cell wastes, has higher requirements on the structure of the scaffold for partial deletion or damage, and has higher requirements on the convenience of operation. The requirement of myocardial injury repair on the stent is not only required to be favorable for adhesion regeneration of myocardial cells, but also required to ensure that the injured part is not further expanded due to stress action, so that the requirement on the degree of contact between the stent material and the shape of the injured part is higher, and more complete and synchronous shape recovery is achieved. However, although some conventional scaffolds for tissue engineering are beneficial to the regeneration of cardiomyocytes, most of the scaffolds for tissue engineering are rigid substances, and the surface tissues of the myocardium transmit signals by contraction and expansion, and meanwhile, the cardiomyocytes have the characteristic of transmitting electrical signals, so that the simple scaffold environment is not beneficial to the recovery of the function of the cardiomyocytes.
The hydrogel is a polymer which has hydrophilic groups, can swell in water and is insoluble in water and has a cross-linked three-dimensional network structure, is an important functional polymer material, and is one of the research hotspots of the current material science. The hydrogel contains hydrophilic groups, can absorb a large amount of water and swell in water, mostly contains higher water content and lower modulus, and can keep the solid property. The hydrogel material can absorb and maintain a large amount of water, is beneficial to the transportation of cell nutrients and metabolites, has adjustable physical and chemical properties, and is widely researched in myocardial tissue engineering. However, the hydrogel with a single component is usually an electrical insulating material, which is not favorable for transmission of electrical signals between cells, and further is not favorable for proliferation of myocardial cells.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the injectable myocardial repair hydrogel and the preparation method thereof, the injectable myocardial repair hydrogel has the conductive characteristic similar to that of myocardial cells, and is beneficial to the transmission of electric signals between the cells; the flexibility of the material is more consistent with that of natural cardiac muscle, and the material is favorable for proliferation of cardiac muscle cells.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides an injectable myocardial repair hydrogel which comprises the following components in parts by weight:
30-60 parts of allyl gelatin, 20-50 parts of oxidized dextran and 3-15 parts of oxidized graphene.
The allyl gelatin can promote the adhesion and proliferation of cells, and can form hydrogel after being crosslinked and cured by ultraviolet light. The oxidized dextran can improve the mechanical property of the allyl gelatin hydrogel after being added into the allyl gelatin, so that the allyl gelatin hydrogel can better conform to the mechanical strength of myocardial tissues. The graphene oxide has good conductivity, and the conductivity of the hydrogel can be improved by adding the graphene oxide into the hydrogel, so that the hydrogel is matched with the electric signal conduction of the surrounding myocardial tissues.
Through a large amount of researches and experiments, the inventor of the invention finds that the prepared hydrogel has the conductive characteristic similar to that of myocardial cells by compounding the allyl gelatin, the oxidized dextran and the oxidized graphene, can provide a signal transmission medium among the myocardial cells, has better cell compatibility, and has an obvious promotion effect on the proliferation of the myocardial cells.
In addition, the hydrogel has mechanical strength similar to that of natural myocardial tissue, has good flexibility, and better conforms to the growth of myocardial cells, thereby being beneficial to the recovery of the function of the myocardial cells; the hydrogel has proper gel time and saves the operation time.
As a preferred embodiment of the injectable myocardial repair hydrogel of the present invention, the injectable myocardial repair hydrogel comprises the following components in parts by weight:
40-60 parts of allyl gelatin, 30-50 parts of oxidized dextran and 6-12 parts of oxidized graphene.
As a preferred embodiment of the injectable myocardial repair hydrogel of the present invention, the injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 10 parts of oxidized graphene.
As a preferred embodiment of the injectable myocardial repair hydrogel according to the present invention, the allyl gelatin is prepared by reacting gelatin with methacrylic anhydride;
the preparation method of the allyl gelatin comprises the following steps:
dissolving gelatin in deionized water at 40-60 ℃ to obtain a gelatin solution with the mass concentration of 5-15%; adding 5-10 ml of methacrylic anhydride into the gelatin solution, uniformly mixing, and reacting at room temperature for 3-5 hours; and after the reaction is finished, adding deionized water, dialyzing, and freeze-drying to obtain the allyl gelatin.
As a preferred embodiment of the injectable myocardial repair hydrogel, the gelatin has a molecular weight of 10-50 ten thousand.
As a preferred embodiment of the injectable myocardial repair hydrogel according to the present invention, the oxidized dextran is prepared by reacting dextran with sodium periodate;
the preparation method of the oxidized glucan comprises the following steps:
dissolving glucan in deionized water to obtain a glucan solution with the mass concentration of 5-10%; adding 50-100 mg/ml sodium periodate into the glucan solution, and oxidizing for 10-24 hours; stopping oxidation reaction with ethylene glycol, dialyzing, and lyophilizing to obtain oxidized dextran.
As a preferred embodiment of the injectable myocardial repair hydrogel of the present invention, the particle size of the graphene oxide is not more than 20 μm.
The invention provides a preparation method of the injectable myocardial repair hydrogel, which comprises the following steps:
s1, dissolving allyl gelatin in water, adding oxidized dextran and oxidized graphene, and uniformly mixing to obtain a mixed solution A;
s2, dissolving a photoinitiator in N-methyl pyrrolidone, and adding the photoinitiator into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by using ultraviolet light to obtain the injectable myocardial repair hydrogel.
The photocuring time of the invention is controllable, so that the hydrogel has better operation convenience when repairing myocardial damage, and simultaneously can improve the filling degree of the damaged part.
As a preferred embodiment of the method for preparing the injectable myocardial repair hydrogel, the photoinitiator is photoinitiator I2959.
As a preferred embodiment of the preparation method of the injectable myocardial repair hydrogel, the wavelength of the ultraviolet light is 365nm, and the irradiation time of the ultraviolet light is 1-5 min.
Compared with the prior art, the invention has the following beneficial effects:
the injectable myocardial repair hydrogel provided by the invention has the conductive characteristic similar to that of myocardial cells, and can provide a signal transmission medium between the myocardial cells; the hydrogel of the invention has better cell compatibility, and the flexibility of the injectable cardiac muscle repair hydrogel is more in line with the natural cardiac muscle, thereby being beneficial to the proliferation of cardiac muscle cells.
Drawings
Fig. 1 is a graph showing the effect of using the injectable myocardial repair hydrogel of the present invention on myocardial cell activity.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
In the following examples, the starting materials used were all commercially available, unless otherwise specified.
1. Preparation of allyl gelatin
The preparation method of the allyl gelatin comprises the following steps:
dissolving 10g of gelatin in 100ml of deionized water, stirring and dissolving at 50 ℃ to obtain a gelatin solution, adding 8ml of methacrylic anhydride into the gelatin solution, uniformly mixing, reacting at room temperature for 3 hours, then stopping the reaction with 300ml of deionized water, dialyzing the solution for one week, and freeze-drying at-80 ℃ for later use.
2. Preparation of oxidized dextran
Dissolving 1g of dextran in 10ml of deionized water to obtain dextran solution, adding 2ml of sodium periodate solution with the concentration of 100mg/ml into the dextran solution, reacting for 20 hours at room temperature in a dark place, stopping the reaction by using ethylene glycol, dialyzing, and freeze-drying for later use.
Example 1 an injectable myocardial repair hydrogel and a method for preparing the same
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 10 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a 50mg/ml solution, adding oxidized dextran and oxidized graphene, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 3min to obtain the injectable myocardial repair hydrogel.
Example 2 injectable myocardial repair hydrogel and preparation method thereof
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
30 parts of allyl gelatin, 40 parts of oxidized dextran and 10 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a solution of 30mg/ml, adding oxidized dextran and oxidized graphene, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 3min to obtain the injectable myocardial repair hydrogel.
Example 3 an injectable myocardial repair hydrogel and a method for preparing the same
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 20 parts of oxidized dextran and 10 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a 50mg/ml solution, adding oxidized dextran and oxidized graphene, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 3min to obtain the injectable myocardial repair hydrogel. The difference from example 1 is that the weight part of the oxidized dextran is 10 parts.
Example 4 injectable myocardial repair hydrogel and preparation method thereof
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 10 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a 50mg/ml solution, adding oxidized dextran and oxidized graphene, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 1min to obtain the injectable myocardial repair hydrogel. The difference from example 1 is that the irradiation time was 1 min.
Example 5 an injectable myocardial repair hydrogel and a method for preparing the same
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 3 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a 40mg/ml solution, adding oxidized dextran, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 5min to obtain the injectable myocardial repair hydrogel.
Example 6 an injectable myocardial repair hydrogel and a method for preparing the same
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 6 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a 60mg/ml solution, adding oxidized dextran, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 3min to obtain the injectable myocardial repair hydrogel.
Example 7 injectable myocardial repair hydrogel and preparation method thereof
The injectable myocardial repair hydrogel comprises the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 15 parts of oxidized graphene.
The preparation method of the injectable myocardial repair hydrogel comprises the following steps:
s1, dissolving allyl gelatin in water to obtain a 50mg/ml solution, adding oxidized dextran, and uniformly mixing to obtain a mixed solution A;
s2, dissolving the photoinitiator I2959 in N-methyl pyrrolidone to obtain a solution with the mass concentration of 0.1%, and adding 20 microliters of the solution into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by adopting ultraviolet light with the wavelength of 365nm for 3min to obtain the injectable myocardial repair hydrogel.
Test example, injectable myocardial repair hydrogel Performance test
The injectable myocardial repair hydrogel obtained in the embodiments 1 to 7 is subjected to in vitro physicochemical property evaluation including gel time, mechanical strength and conductivity under the same environmental conditions by adopting the GB/T16886.5-2017 standard.
And the proliferation of cardiomyocytes by the injectable myocardial repair hydrogel of the present invention was determined according to the following procedure.
1) A suspension of H9C2 cells was prepared.
2) Cell suspensions were seeded in 96-well plates, 5000 cells per well, with at least three replicates per group.
3) The plates were precultured in an incubator for 12,24 and 36 hours (37 ℃, 5% CO 2).
4) Add 10. mu.l of CCK-8 solution to each well.
5) The culture plate is put into an incubator to be incubated for 1-4 h.
6) The absorbance (OD) at 450nm was measured with a microplate reader.
The specific results are shown in tables 1-2 and FIG. 1:
TABLE 1
| Group of | Number of parallel groups | Modulus of elasticity (Kpa) |
| Example 1 | 3 | 120±2.7 |
| Example 2 | 3 | 90±1.3 |
| Example 3 | 3 | 125±2.6 |
| Example 4 | 3 | 78±1.9 |
| Example 5 | 3 | 105±3.1 |
| Example 6 | 3 | 113±1.6 |
| Example 7 | 3 | 132±3.4 |
TABLE 2
According to the tables 1-2, the injectable myocardial repair hydrogel has proper gel time and controllable photocuring time, can facilitate operation of an operation, and can improve the filling degree of an injured part.
The mechanical strength of the injectable myocardial repair hydrogel gel is similar to that of a natural myocardial tissue, the injectable myocardial repair hydrogel has better flexibility, and the hydrogel with the flexibility is more in line with the growth of myocardial cells and is beneficial to the recovery of the function of the myocardial cells.
In addition, the injectable myocardial repair hydrogel prepared in the embodiments 1 to 4 of the present invention has an obvious conductive function, can provide a signal transmission medium between myocardial cells, and has good cellular compatibility. The injectable myocardial repair hydrogel prepared in example 1 has the highest conductivity, and can better provide a signal transmission medium between myocardial cells and promote the recovery of damaged myocardial cells. Compared with the example 1, in the example 4, the ultraviolet light with the wavelength of 365nm is adopted to irradiate the mixed solution B for 1min, and the elastic modulus is changed correspondingly when the irradiation time is changed, which shows that the irradiation time also plays an important role in the elastic modulus of the injectable myocardial repair hydrogel. The injectable myocardial repair hydrogel prepared in examples 5 to 7 has lower conductivity than that of example 1, and when the content of the graphene oxide component is changed, the conductivity of the injectable myocardial repair hydrogel changes, and although the conductivity can be improved by increasing the content of the graphene oxide component, the cell viability can be reduced, and the more the content of the graphene oxide component is, the better the cell viability is, it is shown that the addition of the appropriate content of the graphene oxide can not only improve the conductivity function of the hydrogel, improve the signal transmission medium between myocardial cells, improve the repair effect of myocardial damage, but also improve the activity of the myocardial cells. Referring to fig. 1, the injectable myocardial repair hydrogel prepared by the present invention has a significant effect of promoting proliferation of myocardial cells.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The injectable myocardial repair hydrogel is characterized by comprising the following components in parts by weight:
30-60 parts of allyl gelatin, 20-50 parts of oxidized dextran and 3-15 parts of oxidized graphene.
2. The injectable myocardial repair hydrogel of claim 1 comprising the following components in parts by weight:
40-60 parts of allyl gelatin, 30-50 parts of oxidized dextran and 6-12 parts of oxidized graphene.
3. The injectable myocardial repair hydrogel of claim 1 comprising the following components in parts by weight:
50 parts of allyl gelatin, 40 parts of oxidized dextran and 10 parts of oxidized graphene.
4. The injectable myocardial repair hydrogel of any one of claims 1 to 3, wherein the allyl gelatin is prepared by reacting gelatin with methacrylic anhydride;
the preparation method of the allyl gelatin comprises the following steps:
dissolving gelatin in deionized water at 40-60 ℃ to obtain a gelatin solution with the mass concentration of 5-15%; adding 5-10 ml of methacrylic anhydride into the gelatin solution, uniformly mixing, and reacting at room temperature for 3-5 hours; and after the reaction is finished, adding deionized water, dialyzing, and freeze-drying to obtain the allyl gelatin.
5. The injectable myocardial repair hydrogel of claim 4, wherein the gelatin has a molecular weight of 10 to 50 ten thousand.
6. The injectable myocardial repair hydrogel of any one of claims 1 to 3, wherein the oxidized dextran is prepared by reacting dextran with sodium periodate;
the preparation method of the oxidized glucan comprises the following steps:
dissolving glucan in deionized water to obtain a glucan solution with the mass concentration of 5-10%; adding 50-100 mg/ml sodium periodate into the glucan solution, and oxidizing for 10-24 hours; stopping oxidation reaction with ethylene glycol, dialyzing, and lyophilizing to obtain oxidized dextran.
7. The injectable myocardial repair hydrogel of any one of claims 1 to 3, wherein the graphene oxide has a particle size of not more than 20 μm.
8. A method of preparing an injectable myocardial repair hydrogel according to any one of claims 1 to 7, comprising the steps of:
s1, dissolving allyl gelatin in water, adding oxidized dextran and oxidized graphene, and uniformly mixing to obtain a mixed solution A;
s2, dissolving a photoinitiator in N-methyl pyrrolidone, and adding the photoinitiator into the mixed solution A to obtain a mixed solution B;
and S3, irradiating the mixed solution B by using ultraviolet light to obtain the injectable myocardial repair hydrogel.
9. The method of preparing an injectable myocardial repair hydrogel of claim 8 wherein the photoinitiator is photoinitiator I2959.
10. The method for preparing the injectable myocardial repair hydrogel according to claim 8, wherein the wavelength of the ultraviolet light is 365nm, and the irradiation time of the ultraviolet light is 1-5 min.
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| CN113956509A (en) * | 2021-11-11 | 2022-01-21 | 南京工业大学 | Preparation method and application of gelatin-coupled injectable electrically-conductive composite hydrogel |
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